The microcapsules are particles of substantially spherical shape, of size ranging between 1 and 2000 .mu.m, comprising an inner core constituted by a solution or a dispersion of active ingredient and by an external envelope, generally based on polymers. Such microcapsules are of reservoir type.
Matrice-type microcapsules are also known, more commonly called microspheres, in which the active ingredient is dispersed throughout the particle, within a matrix constituted by a polymer acting as excipient.
The field of the invention is that of reservoir-type microcapsules.
A wide variety of active ingredients can be contained in the microcapsules. There may be medicines, such as antibiotics, virucides or hormones, or immunological agents, such as albumins, interferon, antigens or allergens, or even non-biological agents such as pesticides, detergents, pigments, catalysts or the like.
Said microcapsules can therefore be used in numerous fields such as pharmaceutics, bio-industry, cosmetology, agro-feeding, agro-chemistry, papermaking industry, etc. . .
In therapeutic applications, two methods are possible for using microcapsules.
The first one consists in the controlled and prolonged release of the active ingredient into the medium external to the microcapsule. Besides the requirements of biocompatibility and atoxicity, this using method presupposes that the polymeric external envelope is permeable to the active ingredient and that it allows the outward elution of the latter, according to given and constant kinetics, generally around zero. Said envelope should also be able to preserve its structural integrity against any chemical, biochemical or mechanical aggressions that it may be subjected to in its environment of use.
The second method exploits the capacity of the microcapsules to release instantly and massively the active ingredient, following a mechanical stress of the incision, perforation, crushing type, which induces the breaking, splitting or opening of their external envelope.
In this type of application, which is of particular interest to the invention, the microcapsules are required to have a breaking level which is especially adapted to the factors which will trigger the release of the active ingredient. The polymeric envelope should therefore be strong enough to prevent any premature releases and delicate enough to break up in the required circumstances.
The example whereby microcapsules are included in surgical gloves which are liable to be accidentally perforated by a needle, does illustrate this second method of use of the microcapsules.
Various methods are known which permit the microencapsulation of all types of active ingredients.
For example, U.S. Pat. No. 4,675,189 and European Patent Application No. EP 0 052 610, describe phase separation and coacervation techniques, consisting in using a coacervation agent such as mineral oils or vegetable oils.
Such techniques are very delicate to implement, due to the fact that they often give rise to the formation of cakes which make it difficult to obtain microcapsules.
According to other techniques, called polymerization or interfacial polycondensation techniques, two non-miscible liquid phases are mixed, one of which phases at least contains a polyfunctional reagent capable of inducing a polymerization, such as for example an isocyanate. A polymerization occurs at the interface of the two liquids in a reaction medium which may be an emulsion, then leading to the formation of microcapsules, the wall of which is formed of a polymer of polyamide, polyurethane, polyurea or polyester type.
Patent BE 796 746 describes the encapsulation of lipophilic active ingredients by polymerization of an isocyanate, in an oil-in-water emulsion, for obtaining microcapsules of which the wall is formed of polyurea.
Patent FR 2 548 046 relates to a similar method, permitting the encapsulation of water-soluble substances from an oil-in-water emulsion.
Patent application EP 0 407 257 relates to the encapsulation of water-soluble and amphiphilic substances, such as for example ammoniums, using said interfacial polymerization technique.
The interfacial polymerization is not among the best suited for these last compounds. Indeed, it requires the use of an inner core, as support for the amphiphilic substances, which is based on hydrophobic compounds and which contains high quantities of surface-active agents necessary for stabilizing the medium. Now, said latter do affect the action and efficiency of the active ingredient. Moreover, said surface-active agents do not really prevent the phenomena of agglutination noted during the preparation.
It should also be noted that, in said techniques, the inner core should not contain any products liable to impede the polymerization, for example by reacting with the polymerizing agents, such as the isocyanates. In particular, it is known that polyols, of polyethylene glycol, propylene glycol or glycerol type, are inappropriate as such.
Finally, the microcapsules obtained by this method have a wall which is mechanically inadapted for use with a system of massive and instant release of the active principle.
Other techniques for obtaining microcapsules rely on the formation of a simple oil-in-water emulsion or of a double water-in-oil-in-water emulsion and on the extraction of the solvent from the polymer, in order to solidify the latter. In effect, the polymer forms the phase known as "oily" phase of such emulsions.
In these types of techniques, the active ingredient is, either dispersed into the lipophilic phase containing the polymer in solution in an organic solvent (a simple oil-in-water emulsion), or contained in the internal aqueous phase E.sub.1 of a double water-in-oil-in-water emulsion (E.sub.1 /H/E.sub.2).
International Patent Application WO 90/13 381 describes a method using a double emulsion, in which a solution of polymer in an organic solvent is placed in contact with a non-amphiphilic active ingredient, optionally in aqueous medium, so as to form a first water-in-oil emulsion, called primary emulsion (E.sub.1 /H). Said latter is then introduced into a dispersing medium constituted, preferably, essentially of water and in which a secondary water-in-oil-in-water emulsion (E.sub.1 /H/E.sub.2) can form.
According to this method or to other methods of double emulsion (E.sub.1 /H/E.sub.2) type, the water is preferably used to constitute the internal aqueous phase of the primary E.sub.1 emulsion. Water presents the advantage of being an economical, biocompatible, atoxic and ideal base material for the formation of emulsions. Appreciably, it is also, in most cases, inert and compatible towards water-soluble and amphiphilic active ingredients, with which the invention is more particularly concerned.
Yet, its use is not without raising problems with regard to the application of the microcapsules to systems of instant and massive release of the active ingredient, in which the active ingredient has to be very readily available and efficient towards the target.
Indeed, in this application, the microcapsules are embedded in an elastomer which forms the constituent material of the considered article, which may be surgical gloves. Now, crosslinking of the elastomer which occurs in the production of such articles, is achieved at high temperature, around 120.degree. C. As a result, the inner aqueous core of the microcapsules containing the active ingredient evaporates, thus reducing considerably the efficiency of the active ingredient once the wall has been broken.